FASN inhibitor for MASH with fibrosis gets a pass to phase III

The oral fatty acid synthase (FASN) inhibitor denifanstat appears to produce meaningful improvements in metabolic dysfunction-associated steatohepatitis (MASH) and stage 2–3 fibrosis, as shown in the results of a phase IIb trial.

In an intention-to-treat (ITT) analysis, 38 percent of patients on denifanstat met the primary endpoint of at least a 2-point improvement in nonalcoholic fatty liver disease activity score (NAS) without worsening of fibrosis at week 52 compared with 16 percent of those on placebo (common risk difference, 21.0 percent, 95 percent confidence interval [CI], 8.1–33.9; p=0.0035). [Lancet Gastroenterol Hepatol 2024;doi:10.1016/S2468-1253(24)00246-2]

The other primary endpoint of MASH resolution and at least a 2-point improvement in NAS without worsening of fibrosis at week 52 was also met with significantly higher frequency with denifanstat than with placebo (26 percent vs 11 percent; common risk difference, 13.0 percent, 95 percent CI, 0.7–25.3; p=0.0173).

“Denifanstat directly targets three of the major pathways responsible for liver injury via direct inhibition of endogenous FASN activity in hepatocytes, immune cells, and stellate cells,” the investigators noted. “The results of this study, notably an improvement in fibrosis without worsening of steatohepatitis in around 20 percent more participants in the denifanstat group than in the placebo group, show the potential impact this unique mechanism could have in treating MASH.”

Other endpoints

Aside from meeting the primary endpoints, denifanstat was also associated with significant improvements in other endpoints.

In the modified ITT (mITT) population, significantly more patients treated with denifanstat vs placebo achieved fibrosis improvement by one stage or more without worsening of steatohepatitis (p=0.0102), fibrosis improvement by two or more stages without worsening of steatohepatitis (p=0.0065), MASH resolution without worsening of fibrosis (p=0.0043), and reductions in qFibrosis score (p=0.0142) and liver fat (p=0.0008), among others.

“The mITT population (ie, participants who had both pretreatment and post-treatment biopsies) provides evidence of the direct effect of denifanstat's mechanism of action on the liver in individuals with MASH… The number needed to treat for either MASH resolution or fibrosis improvement is 6 in the ITT population and 4 in the mITT population,” the investigators said.

“Denifanstat also increased the level of polyunsaturated fatty acids in triglycerides and reduced LDL cholesterol, suggesting it might have beneficial cardiometabolic effects,” they added.

Safety

The FASN inhibitor was generally well-tolerated. The most frequently reported treatment-emergent adverse events (AEs) were COVID-19 (17 percent with denifanstat vs 11 percent with placebo), dry eye symptoms (9 percent vs 14 percent, respectively), and alopecia (19 percent vs 4 percent, respectively).

Serious AEs occurred in 12 percent of patients in the denifanstat group vs 5 percent of those in the placebo group, none of which were deemed to be related to the study drug. All drug-related AEs were of grade 1 or 2 in severity.

“These results show the importance of targeting liver inflammation and fibrosis directly. Phase III studies of denifanstat in patients with MASH and stage 2 to stage 3 fibrosis are planned to further characterize the safety and efficacy of this drug in a larger number of patients across multiple countries and assess its impact on longer term outcomes,” the investigators said. “These studies will pave the way to potentially make this drug available to patients with MASH with moderate-to-advanced fibrosis.”

The phase IIb study included 168 patients (mean age 57 years, 60 percent female, 89 percent White) who were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All of them received at least one dose of study treatment. A total of 45 patients in the placebo group and 81 patients in the denifanstat group had post-treatment biopsies and were included in the mITT population. Common background medications included statins (51 percent) and GLP-1 RAs (14 percent).